A. We have recently discovered a specific receptor for the mammalian bombesin related peptide, Neuromedin B (NMB). In this study we have identified high affinity receptors on the rat glioblastoma tumor cell line, C-6 and we have investigated the cellular basis of action of peptides at this receptor in this cell line. The high affinity NMB receptors on C-6 cells pharmacologically were identical to those in normal tissues. NMB increased phospholipase C activity, increasing cellular calcium and phosphoinositides including IP1, IP2 and IP3. No alterations in cAMP were seen. Similar results were found in collaboration with Dr. T.W. Moody (George Washington University) in human small cell lung cancer cells. These results show that both receptors for the mammalian Bn peptides NMB and GRP have similar cellular transduction mechanisms in that both activate phospholipase C. B. The cellular basis of action of the structurally related peptides gastrin and cholecystokinin on stimulating pepsinogen release from chief cells is unclear and was investigated in the present study. Each peptide increased the mobilization of cellular calcium and increased IP3. However, they differed in their efficacy, stoichiometry and intracellular coupling. Detailed analysis demonstrated that these 2 peptides were altering cellular function by interacting with 2 distinct receptors with different coupling mechanisms. C. To investigate the role of extracellular and intracellular calcium in secretagogue-induced enzyme secretion in pancreatic acini, we studied the ability of thapsigargin (TG), an inhibitor of microsomal calcium ATPase to alter secretagogue stimulated secretion and [Ca2+]i levels. Our findings indicate that stimulation of enzyme secretion by secretagogues that increase IP3 (1,4,5) does not depend on increases in [Ca2+]i per se. In contrast, TG-induced potentiation of stimulation of secretagogues that increase cAMP results from increased free [Ca2+]i.